Decreased coumarin 7-hydroxylase activities and CYP2A6 expression levels in humans caused by genetic polymorphism in CYP2A6 promoter region (CYP2A6*9)

Kiyotani, Kazuma, Yamazaki, Hiroshi, Fujieda, Masaki, Iwano, Shunsuke, Matsumura, Keiko, Satarug, Soisungwan, Ujjin, Pailin, Shimada, Tsutomu, Guengerich, F Peter, Parkinson, Andrew, Honda, Goro, Nakagawa, Kazuko, Ishizaki, Takashi and Kamataki, Tetsuya (2003) Decreased coumarin 7-hydroxylase activities and CYP2A6 expression levels in humans caused by genetic polymorphism in CYP2A6 promoter region (CYP2A6*9). Pharmacogenetics, 13 11: 689-695.

Author Kiyotani, Kazuma
Yamazaki, Hiroshi
Fujieda, Masaki
Iwano, Shunsuke
Matsumura, Keiko
Satarug, Soisungwan
Ujjin, Pailin
Shimada, Tsutomu
Guengerich, F Peter
Parkinson, Andrew
Honda, Goro
Nakagawa, Kazuko
Ishizaki, Takashi
Kamataki, Tetsuya
Title Decreased coumarin 7-hydroxylase activities and CYP2A6 expression levels in humans caused by genetic polymorphism in CYP2A6 promoter region (CYP2A6*9)
Formatted title Decreased coumarin 7-hydroxylase activities and CYP2A6 expression levels in humans caused by genetic polymorphism in CYP2A6 promoter region (CYP2A6*9)
Journal name Pharmacogenetics   Check publisher's open access policy
ISSN 0960-314X
Publication date 2003-11
Sub-type Article (original research)
Volume 13
Issue 11
Start page 689
End page 695
Total pages 7
Place of publication Philadelphia, USA
Publisher Lippincott Williams & Wilkins
Collection year 2003
Language eng
Subject C1
321299 Public Health and Health Services not elsewhere classified
730299 Public health not elsewhere classified
Abstract One of seven poor metabolizers of coumarin found in Thai subjects was previously genotyped as heterozygote for the CYP2A6*4 (whole deletion) and CYP2A6*9. Thus, we aimed to investigate the relationship between the genetic polymorphism in the TATA box of the CYP2A6 gene (CYP2A6*9), expression levels of CYP2A6 mRNA and coumarin 7-hydroxylase activities in human livers. Levels of CYP2A6 mRNA were quantified by real-time quantitative reverse transcriptase-polymerase chain reaction. The mean expression levels of CYP2A6 mRNA in individuals with CYP2A6*1/*4, CYP2A6*1/*9 and CYP2A6*4/*9 were 58%, 71% and 21% of the individuals genotyped as CYP2A6*1/*1, respectively. The mean in-vitro coumarin 7-hydroxylase activities in subjects carrying CYP2A6*1/*4, CYP2A6*1/*9 and CYP2A6*4/*9 were 41%, 71% and 12%, respectively, compared to those of the subjects judged as wild-type. Vmax values for coumarin 7-hydroxylation in the liver microsomes from human subjects with genotypes of CYP2A6*1/*1, CYP2A6*1/*4, CYP2A6*1/*9 and CYP2A6*4/*9 were 0.58, 0.26, 0.44 and 0.13 nmol/min/nmol total P450, respectively. CYP2A6 protein levels in human liver microsomes with the CYP2A6*4 and the CYP2A6*9 alleles were markedly decreased. These results suggest that the genetic polymorphism in the promoter region of the CYP2A6 gene (CYP2A6*9) reduced the expression levels of CYP2A6 mRNA and protein in human livers, resulting in the decrease of coumarin 7-hydroxylase activities. Individuals judged as CYP2A6*4/*9 were expected to be poor metabolizers, having extremely low activity of CYP2A6.
Keyword P450 2A6
SNP
7-hydroxycoumarin
poor metabolizer
TATA box
Q-Index Code C1

 
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Created: Wed, 15 Aug 2007, 01:50:38 EST